Cancer is a disease of abnormal and uncontrolled cell growth. Cancer cells are also genetically unstable and subject to frequent mutations, resulting in a heterogeneous mixture of cancer cells, some of which are resistant to chemotherapeutic treatments. While rounds of chemotherapy may eliminate most of the cancer cells in a patient, the chemotherapy also becomes a selection mechanism for chemo-resistant cancer cells. Relapses in cancer patients are thought to occur because a small number of cancer cells survive by accumulating mutations that make them resistant to the chemotherapeutic agent being used.
Combination chemotherapy combines two or more chemotherapeutic agents to attack cancer cells by targeting different physiological targets (e.g., mechanisms of action) and/or life cycles of the cancer cell, with minimal cross resistance between the agents in order to decrease the likelihood that the cancer cells can survive the combination therapy. One primary rationale for combination chemotherapy in cancer treatment is that the probability of developing all of the mutations that confer resistance in a single cancer cell to all of the chemotherapeutic agents of the combination is much lower than the probability of accumulating mutations conferring resistance to a single chemotherapeutic agent. Combination therapy can also allow use of lower doses of a chemotherapeutic agent because two or more agents attack the cancer cell in concert, and may also enhance patient compliance if the chemotherapeutic agents are provided in a single composition.
Despite the advantages of combination therapies, the development of specific chemotherapy combinations that are effective against cancers is difficult because of the unpredictable effects of targeting different biological targets and the lack of information on the biochemical and molecular mechanisms of drug interaction at the cellular level. It is difficult to determine whether a specific drug combination will be synergistic (i.e., superior), simply additive (i.e., equal), or even antagonistic (i.e., inferior). Some chemotherapy combinations having a synergistic response at one ratio can be antagonistic when used in a different ratio.